4m48: Difference between revisions
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==X-ray structure of dopamine transporter elucidates antidepressant mechanism== | |||
=== | <StructureSection load='4m48' size='340' side='right' caption='[[4m48]], [[Resolution|resolution]] 2.96Å' scene=''> | ||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[4m48]] is a 3 chain structure with sequence from [http://en.wikipedia.org/wiki/Drome Drome] and [http://en.wikipedia.org/wiki/Mus_musculus Mus musculus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4M48 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4M48 FirstGlance]. <br> | |||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=21B:NORTRIPTYLINE'>21B</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=CLR:CHOLESTEROL'>CLR</scene>, <scene name='pdbligand=NA:SODIUM+ION'>NA</scene></td></tr> | |||
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">DAT, CG8380 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=7227 DROME])</td></tr> | |||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4m48 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4m48 OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4m48 RCSB], [http://www.ebi.ac.uk/pdbsum/4m48 PDBsum]</span></td></tr> | |||
</table> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Antidepressants targeting Na+/Cl--coupled neurotransmitter uptake define a key therapeutic strategy to treat clinical depression and neuropathic pain. However, identifying the molecular interactions that underlie the pharmacological activity of these transport inhibitors, and thus the mechanism by which the inhibitors lead to increased synaptic neurotransmitter levels, has proven elusive. Here we present the crystal structure of the Drosophila melanogaster dopamine transporter at 3.0 A resolution bound to the tricyclic antidepressant nortriptyline. The transporter is locked in an outward-open conformation with nortriptyline wedged between transmembrane helices 1, 3, 6 and 8, blocking the transporter from binding substrate and from isomerizing to an inward-facing conformation. Although the overall structure of the dopamine transporter is similar to that of its prokaryotic relative LeuT, there are multiple distinctions, including a kink in transmembrane helix 12 halfway across the membrane bilayer, a latch-like carboxy-terminal helix that caps the cytoplasmic gate, and a cholesterol molecule wedged within a groove formed by transmembrane helices 1a, 5 and 7. Taken together, the dopamine transporter structure reveals the molecular basis for antidepressant action on sodium-coupled neurotransmitter symporters and elucidates critical elements of eukaryotic transporter structure and modulation by lipids, thus expanding our understanding of the mechanism and regulation of neurotransmitter uptake at chemical synapses. | |||
X-ray structure of dopamine transporter elucidates antidepressant mechanism.,Penmatsa A, Wang KH, Gouaux E Nature. 2013 Sep 15. doi: 10.1038/nature12533. PMID:24037379<ref>PMID:24037379</ref> | |||
== | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | ||
</div> | |||
==See Also== | |||
*[[Antibody|Antibody]] | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Drome]] | [[Category: Drome]] | ||
[[Category: Mus musculus]] | [[Category: Mus musculus]] | ||
[[Category: Gouaux, E | [[Category: Gouaux, E]] | ||
[[Category: Penmatsa, A | [[Category: Penmatsa, A]] | ||
[[Category: Wang, K | [[Category: Wang, K]] | ||
[[Category: Neurotransmitter transporter]] | [[Category: Neurotransmitter transporter]] | ||
[[Category: Slc6]] | [[Category: Slc6]] | ||
[[Category: Transport protein]] | [[Category: Transport protein]] | ||
Revision as of 12:41, 5 January 2015
X-ray structure of dopamine transporter elucidates antidepressant mechanismX-ray structure of dopamine transporter elucidates antidepressant mechanism
Structural highlights
Publication Abstract from PubMedAntidepressants targeting Na+/Cl--coupled neurotransmitter uptake define a key therapeutic strategy to treat clinical depression and neuropathic pain. However, identifying the molecular interactions that underlie the pharmacological activity of these transport inhibitors, and thus the mechanism by which the inhibitors lead to increased synaptic neurotransmitter levels, has proven elusive. Here we present the crystal structure of the Drosophila melanogaster dopamine transporter at 3.0 A resolution bound to the tricyclic antidepressant nortriptyline. The transporter is locked in an outward-open conformation with nortriptyline wedged between transmembrane helices 1, 3, 6 and 8, blocking the transporter from binding substrate and from isomerizing to an inward-facing conformation. Although the overall structure of the dopamine transporter is similar to that of its prokaryotic relative LeuT, there are multiple distinctions, including a kink in transmembrane helix 12 halfway across the membrane bilayer, a latch-like carboxy-terminal helix that caps the cytoplasmic gate, and a cholesterol molecule wedged within a groove formed by transmembrane helices 1a, 5 and 7. Taken together, the dopamine transporter structure reveals the molecular basis for antidepressant action on sodium-coupled neurotransmitter symporters and elucidates critical elements of eukaryotic transporter structure and modulation by lipids, thus expanding our understanding of the mechanism and regulation of neurotransmitter uptake at chemical synapses. X-ray structure of dopamine transporter elucidates antidepressant mechanism.,Penmatsa A, Wang KH, Gouaux E Nature. 2013 Sep 15. doi: 10.1038/nature12533. PMID:24037379[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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